Diffuse large B-cell lymphoma (DLBCL) is a cancer of B cells and is the most common type of non-Hodgkin's lymphoma among adults. DLBCL is an aggressive tumor which can arise in almost any part of the body. Typically, DLBCL arises from normal B cells, but it can also represent a malignant transformation of other types of lymphoma or leukemia with underlying immunodeficiency being a significant risk factor. Despite advances in treatment, one third of DLBCL patients either do not respond or relapse within a short time. There are two major biologically distinct molecular subtypes of DLBCL: germinal center B-cell (GCB) and activated B-cell (ABC). ABC-DLBCL is derived from B cells that are in the process of differentiating from germinal center B cells to plasma cells. Typically, patients diagnosed with the ABC sybtype have poorer outcomes than GCB patients.
Mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) is part of the paracaspase family and possesses proteolytic activity. It has an important role in the activation of the transcription factor NF-κB, in the production of interleukin-2 (IL-2), and in the proliferation of T and B lymphocytes. For example, the survival of several known ABC-DLBCL cell lines depends on a trio of signaling adapters: CARD11, MALT1, and BCL10. These proteins form the CBM complex that is involved in the antigen-dependent activation of NF-κB. In addition to acting as a scaffold protein within the CBM complex, MALT1 also contains a proteolytic activity that is constitutively activated in ABC-DLBCL. MALT1 inhibitors are known to inhibit NF-κB target gene expression and ABC-DLBCL viability, making MALT1 inhibition an attractive therapeutic target for the treatment of ABC-DLBCL.
E3 ubiquitin ligases are proteins that, in combination with an E2 ubiquitin-conjugating enzyme, promote the attachment of ubiquitin to a lysine on a target protein via an isopeptide bond (e.g., an amide bond that is not present on the main chain of a protein). The ubiquitination of the protein commonly results in degradation of the target protein by the proteasome.
The von Hippel-Lindau tumor suppressor (VHL) is an E3 ubiquitin ligase. VHL comprises the substrate recognition subunit/E3 ubiquitin ligase complex VCB, which includes elongins B and C, and a complex including Cullin-2 and Rbx1. The primary substrate of VHL is Hypoxia Inducible Factor 1α (HIF-1α), a transcription factor that upregulates genes, such as the pro-angiogenic growth factor VEGF and the red blood cell-inducing cytokine, erythropoietin, in response to low oxygen levels. VCB is a known target in cancer, chronic anemia, and ischemia.
Cereblon (CRBN) is another E3 ubiquitin ligase, and it forms an E3 ubiquitin ligase complex with damaged DNA binding protein 1 (DDB 1), Cullin-4A (CUL4A), and regulator of cullins 1 (ROC 1). This complex ubiquitinates a number of other proteins. Through a mechanism which has not been completely elucidated, Cereblon ubiquitination of target proteins results in increased levels of fibroblast growth factor 8 (FGF8) and fibroblast growth factor 10 (FGF10). FGF8, in turn, regulates a number of developmental processes, such as limb and auditory vesicle formation. In addition, studies suggest that small molecules that bind and inhibit Cereblon (e.g., lenalidomide) have direct antitumor activity against DLBCL cells, preferentially ABC-DLBCL cells.
An ongoing need exists to identify drugs that effectively treat cancers, such as DLBCL. In particular, drugs that can take advantage of cellular machinery involved in protein homeostasis (e.g., ubiquitination) may find particular use as therapeutic agents.